1. Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

2. TRANSCRIPTION FACTORS Tímea Berki and Ferenc Boldizsár Signal transduction Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

3. TÁMOP-4.1.2-08/1/A-2009-0011 Structural groups of transcription factors Helix-loop-helix eg. MyoD, c-Myc Leucin zippers eg. AP-1, CREB Zinc-coordinating DNA-binding domains eg. Zinc fingers: nuclear receptors for steroids, thyroid hormone; GATA factors Helix-turn-helix eg. Homeobox; Forkhead / winged helix Beta-scaffold factors with minor groove contacts eg. NF  B, NFAT, STAT, p53 Others

4. TÁMOP-4.1.2-08/1/A-2009-0011 Structural groups of transcription factors C C H H C C H H DNA binding Zinc finger transcription factors Transactivation Zn Basic helix-loop-helix Helix DNA-binding domain DNA-binding domain Loop H2NH2NNH 2 Basic leucine zipper

5. TÁMOP-4.1.2-08/1/A-2009-0011 Functional domains of transcription factors Ligand A/BCE F D N-terminal domain Hinge regionC-terminal domain DNA binding domain (DBD) Ligand binding domain (LBD) Dimerization Transactivation

6. TÁMOP-4.1.2-08/1/A-2009-0011 Nuclear receptor superfamily GR Steroid Recetors Glucocorticoid Mineralocorticoid Progesterone Androgen GR MR PR AR Dimeric Orphan Receptors RXR COUP HNF-4 TR2 TLX GCNF 9-cis RA RXR Monomeric/Tethered Orphan Receptors NGFI-B SF-1 Rev-erb ROR ERR RXR T3R RAR VDR PPAR  PPAR  EcR FXR CAR LXR PXR/SXR RXR Heterodimers Thyroid hormone All-trans RA 1,2,5-(OH)2-VD Fatty acids 15d-  12,14 -PGJ Ecdysone Bile acids Androstane Oxysterol Xenobiotics RXR R

7. TÁMOP-4.1.2-08/1/A-2009-0011 Mechanism of steroid receptor action HSP GR HSP GR HRE Co-activator RNA polymerase GR Co-activator RNA polymerase Co-activator RNA polymerase RXRR HRE Co-activator RNA polymerase Co-activator RNA polymerase HRE RXR Co-repressor Hormone Nucleus Plasma membrane Cytoplasm Co-repressor RXRR HRE Transcription

8. TÁMOP-4.1.2-08/1/A-2009-0011 Functional groups of TFs General transcription factors: constitutively active, present in all cells at all times, bind TATA box, form preinitiation complex eg. TFIIA-H Specific transcription factors /upstream transcription factors are conditionally active –Developmental (cell specific) eg. GATA, MyoD, Hox, Winged helix –Signal-dependent

9. TÁMOP-4.1.2-08/1/A-2009-0011 Signal-dependent TFs Extracellular ligand (eg. nuclear receptors) Intracellular ligand (eg. SREBP, p53) Cell-membrane receptor dependent Resident nuclear (eg. CREB, AP-1, Mef-2) Latent cytoplasmic (eg. STAT, NFAT, NF  B, Notch)

10. TÁMOP-4.1.2-08/1/A-2009-0011 TFs in T cell activation induce cytokine productionTCR    CD28 Plasma membrane Calcium flux, NFAT activation Calcium flux, NFAT activation MAPK activation, AP1 formation MAPK activation, AP1 formation GRB2 SOS RAS GRP1 RAS GRP1 DAG GTPGTP NFAT IL-12 Nucleus ZAP70 AP1 CD3

11. TÁMOP-4.1.2-08/1/A-2009-0011 Structure of STATs NH 2 Coiled coilDBDLkSH 2 TAD Y P 0200400600800

12. TÁMOP-4.1.2-08/1/A-2009-0011 Regulation of transcription Transcriptional control Transcription factors, chromatin state, combinatorial control, co-factors, alternative promoters, etc. Transcriptional control Transcription factors, chromatin state, combinatorial control, co-factors, alternative promoters, etc. Post-transcriptional control MicroRNAs, alternative splicing, alternative polyadenylation, RNA-binding proteins, etc. Post-transcriptional control MicroRNAs, alternative splicing, alternative polyadenylation, RNA-binding proteins, etc. miRNAs mRNAs TF

13. TÁMOP-4.1.2-08/1/A-2009-0011 Mechanism of gene regulation General transcription factors and the RNA Polymerase interacts with numerous coregulators (specific transcription factors) Activators bind to enhancer elements Repressors bind to silencer elements of the DNA upstream from the TATA box

14. TÁMOP-4.1.2-08/1/A-2009-0011 Growth factor induced TFs and their biological effect Cell survival Proliferation Apoptosis resistance Metastasis Angiogenesis SOS GRB2 Ras Rac Rho CDC42 MEK1/2 Erk Raf ERK pathway MKK4/7 JNK MEKK JNK pathway MKK3/6 p38 Tak p38 pathway Akt mTor PI3K HER2

15. TÁMOP-4.1.2-08/1/A-2009-0011 Some important transcription factors FamilyRepresentative transcription factorsFunctions Homeodomain HoxHoxa-1, Hoxb-2, etc.Axis formation POUPit-1, Unc-86, Oct-2Pituitary development; neural fate LIMLim-1, ForkheadHead development PaxPax1, 2, 3, etc.Neural specification; eye development Basic helix-loop-helix (bHLH)MyoD, achaete, daughterless Muscle and nerve specification; Drosophila sex determination Basic leucine zipper (bZip)C/EBP, AP1Liver differentiation; fat cell specification Zinc finger StandardWT1, Krüppel, Engrailed Kidney, gonad, and macrophage development; Drosophila segmentation Nuclear hormone receptors Glucocorticoid receptor, estrogen receptor, testosterone receptor, retinoic acid receptors Secondary sex determination; craniofacial development; limb development Sry-SoxSry, SoxD, Sox2 Bend DNA; mammalian primary sex determination; ectoderm differentiation

16. TÁMOP-4.1.2-08/1/A-2009-0011 Transcription factors and diseases IPEX syndrome (Immunodysregulation Polyendocrinopathy Enteritis X-linked), “Scurfy” phenotype in mouse: FoxP3 Rett-syndrome: MECP2 Li-Fraumeni-syndrome: p53